Cortical bone strength is critical to skeletal integrity. Cortical microstructure, in particular porosity, has a significant impact on mechanical properties of the cortex. Additionally, cortical bone microstructure is responsive to disease, therapy, and metabolic alterations. Therefore the investigation of cortical microstructure is an important aspect of understanding biological, pathoetiological, and biomechanical processes occurring within the skeleton. The mechanisms driving increased cortical porosity are unknown. Our central hypothesis is that cortical pore space contents may be an indicator of pore expansion mechanisms. Marrow within a pore may indicate endocortical 'trabecularization', or an expansion of the marrow cavity into the cortical envelope. Vessel and hematopoietic components within pore space may indicate the formation of large pores via merging or expansion of the vascular network. In the long term, characterizing pore space constituents and understanding pore expansion mechanisms may aid in the development of strategies to prevent or reverse increased porosity and the associated bone fragility. The overall goal of this research is to develop a technique for in vivo visualization and quantification of cortical porosity and por content, and to apply this technique to a longitudinal data set. We will characterize pore content using in vivo imaging techniques, specifically high resolution peripheral quantitative computed tomography (HR-pQCT) and magnetic resonance (MR) imaging. HR-pQCT enables 3D visualization of cortical microstructure. MR provides 3D visualization and discrimination of fat and water components. The specific aims are to: I) develop and verify pore space content characterization by combined HR-pQCT and MR imaging and II) quantify longitudinal changes in porosity and pore space content by combined HR-pQCT and MR imaging. To address Aim I, combined HR-pQCT and MR analysis will be applied using both conventional and advanced MR techniques in cadaveric tibiae. Histological analysis will be performed to confirm the composition of pore space contents in regions determined by imaging to contain marrow fat and vascular components. To address Aim II, an existing longitudinal data set will be analyzed and longitudinal changes in porosity and distribution of marrow fat and vascular components within the cortical pore space will be quantified. This work will develop in vivo characterization of cortical pore constituents in a longitudinal setting, and will provide pilot data on advanced imaging techniques for future in vivo studies investigating mechanisms of increased cortical porosity. The identification of mechanisms of increased cortical porosity will direct the development of targeted treatments, possibly through osteoblastogenic or anti-angiogenic therapy.